In spite of several novel drugs for metastatic melanoma entering the market in the last few years, there is an enormous need for novel effective treatments that would not rely on patients' specific genotypes, biochemical pathways or the variability of an individual?s immune response. Previously we conducted a successful Phase 1 clinical trial of an antibody to melanin radiolabeled with beta emitter 188Rhenium. However, the IgM isotype of that antibody presented an impediment to further clinical development. Recently we have identified a novel antibody to melanin with the IgG isotype which can be easily humanized for future clinical trials. The long-term goal of the proposal is to develop and bring to the market the radioimmunotherapy of metastatic melanoma based on this novel IgG to melanin. We are planning the following Aims: 1) Perform the conjugation of 8C3 IgG with the chelating agents to enable radiolabeling with alpha- and beta-emitting therapeutic radionuclides; 2) Carry out pharmacokinetics/pharmacodynamics studies of radiolabeled 8C3 in murine and human melanoma models. Use the data from these studies to perform radiation dosimetry calculations; 3) Perform proof-of-concept RIT experiments in murine and human melanoma models. Assess the efficacy and short-term toxicity of the treatment. We anticipate that both beta- and alpha-emitting radionuclide radiolabeled IgG to melanin will be effective in slowing down or abrogating experimental tumor growth and also safe towards all major organs. Based on the realistic estimates of radionuclides commercial availability, we will make the selection of the most suitable radiolabeled form of IgG to melanin for the future IND enabling experiments.